Ion Channels Controlling Circadian Rhythms in Suprachiasmatic Nucleus Excitability

Abstract

Animals synchronize to the environmental day-night cycle by means of an internal circadian clock in the brain. In mammals, this timekeeping mechanism is housed in the suprachiasmatic nucleus (SCN) of the hypothalamus and is entrained by light input from the retina. One output of the SCN is a neural code for circadian time, which arises from the collective activity of neurons within the SCN circuit and comprises two fundamental components: 1) periodic alterations in the spontaneous excitability of individual neurons that result in higher firing rates during the day and lower firing rates at night, and 2) synchronization of these cellular oscillations throughout the SCN. In this review, we summarize current evidence for the identity of ion channels in SCN neurons and the mechanisms by which they set the rhythmic parameters of the time code. During the day, voltage-dependent and independent Na+ and Ca2+ currents, as well as several K+ currents, contribute to increased membrane excitability and therefore higher firing frequency. At night, an increase in different K+ currents, including Ca2+-activated BK currents, contribute to membrane hyperpolarization and decreased firing. Layered on top of these intrinsically regulated changes in membrane excitability, more than a dozen neuromodulators influence action potential activity and rhythmicity in SCN neurons, facilitating both synchronization and plasticity of the neural code.

Ethanol’s interaction with BK channel α subunit residue K361 does not mediate behavioral responses to alcohol in mice

“…Finally, given the role of BK channels in regulating neuronal excitability in the suprachiasmatic nucleus (the primary circadian pacemaker in mammals) [37, 38] and the desynchronization of biological rhythms observed in AUD [39, 40], we sought to determine whether the action of ethanol on BK channels could be responsible for a disruption of circadian rhythmicity in CIE-exposed mice. Under a standard light-dark cycle, the ambulation of CIE-exposed mice was significantly reduced up to withdrawal day 8 (vapor × time interaction: F 13,156 =10.3, p<0.0001, see Fig.…”

Daily electrical activity in the master circadian clock of a diurnal mammal

“…Most importantly, the fundamental daily rhythm in electrical excitability ('upstate' during the day and a 'downstate' at night (Allen et al, 2017;Belle & Diekman, 2018;Harvey et al, 2020)) reported for nocturnal species is retained in R. pumilio. This reinforces the current view that mechanisms of rhythm generation and regulation are broadly retained across mammalian species with different circadian niches.…”

“…Our current understanding of SCN neurophysiology comes overwhelmingly from electrophysiological recordings on a small number of nocturnal rodent species (mice, rats and hamsters) (Colwell, 2011;Belle & Diekman, 2018;Harvey et al, 2020). A handful of studies have confirmed that the daytime peak in spontaneous activity (as reflected in extracellular electrical activity or deoxyglucose uptake) is retained in the SCN of diurnal species (Sato & Kawamura, 1984;Schwartz, 1991;Ruby & Heller, 1996).…”

Suprachiasmatic nucleus-dependent and independent outputs driving rhythmic activity in hypothalamic and thalamic neurons

“…While there are local clocks across the brain and body that contribute to these processes, the maintenance of robust whole animal physiological timing and its coordination with environmental cycles relies on a master clock located in the hypothalamic suprachiasmatic nuclei (SCN) [3][4][5]. Hence, the molecular clock in SCN neurons drives circadian variation in membrane excitability and electrical output, and retinal inputs to the SCN align these neuronal oscillators to transmit high amplitude timing signals to their downstream targets [6,7].…”